tbuckley/cabot-search huggingface dataset:
The First High-Quality Reference Genome of Sika Deer Provides Insights into High-Tannin Adaptation
Authors: Xiumei Xing, Cheng Ai, Tianjiao Wang, Yang Li, Huitao Liu, Pengfei Hu, Guiwu Wang, Huamiao Liu, Hongliang Wang, Ranran Zhang, Junjun Zheng, Xiaobo Wang, Lei Wang, Yuxiao Chang, Qian Qian, Jinghua Yu, Lixin Tang, Shigang Wu, Xiujuan Shao, Alun Li, Peng Cui, Wei Zhan, Sheng Zhao, Zhichao Wu, Xiqun Shao, Yimeng Dong, Min Rong, Yihong Tan, Xuezhe Cui, Shuzhuo Chang, Xingchao Song, Tongao Yang, Limin Sun, Yan Ju, Pei Zhao, Huanhuan Fan, Ying Liu, Xinhui Wang, Wanyun Yang, Min Yang, Tao Wei, Shanshan Song, Jiaping Xu, Zhigang Yue, Qiqi Liang, Chunyi Li, Jue Ruan, Fuhe Yang
Journal: Genomics Proteomics & Bioinformatics (2022)

Abstract Sika deer are known to prefer oak leaves, which are rich in tannins and toxic to most mammals; however, the genetic mechanisms underlying their unique ability to adapt to living in the jungle are still unclear. In identifying the mechanism responsible for the tolerance of a highly toxic diet, we have made a major advancement by explaining the genome of sika deer. We generated the first high-quality, chromosome-level genome assembly of sika deer and measured the correlation between tannin intake and RNA expression in 15 tissues through 180 experiments. Comparative genome analyses showed that the UGT and CYP gene families are functionally involved in the adaptation of sika deer to high-tannin food, especially the expansion of the UGT family 2 subfamily B of UGT genes. The first chromosome-level assembly and genetic characterization of the tolerance to a highly toxic diet suggest that the sika deer genome may serve as an essential resource for understanding evolutionary events and tannin adaptation. Our study provides a paradigm of comparative expressive genomics that can be applied to the study of unique biological features in non-model animals.
Abstract 2621: Growth hormone receptor antagonist sensitizes melanoma and hepatocarcinoma to drug treatments via downregulation of ABC transporters in vivo
Authors: Yanrong Qian, Reetobrata Basu, Samuel Mathes, Prateek Kulkarni, Emily Davis, Darlene Berryman, Edward List, Silvana Duran, John J. Kopchick
Journal: Cancer Research (2022)

Abstract Knockdown of the growth hormone receptor (GHR) in melanoma cells downregulates ATP-binding cassette (ABC) transporters and sensitizes them to multiple drug treatments in vitro. The goal for this study is to understand whether a GHR antagonist (GHA) could suppress different types of cancers by sensitizing tumors to drug treatments in vivo through the downregulation of ABC transporters. Sera from GHA transgenic mice inhibited the proliferation of mouse melanoma cells (B16F10) in culture and suppressed expression of multiple ABC transporters. When B16-F10 cells were intradermally inoculated into GHA mice, tumor size was markedly reduced, as was STAT5 activation and ABCG1, ABCG2 levels. We then tested the effect of the GHA on the efficacy of cisplatin in vivo. GHA sensitized melanomas to cisplatin, leading to the smallest tumors among all groups. GHKO mice showed the same effect. We further extended this investigation to hepatocellular carcinoma (HCC). GHA mice were subcutaneously inoculated with mouse HCC (Hepa1 6 cells) and subsequently treated with sorafenib. The HCC tumors in GHA mice were markedly sensitive to sorafenib treatment compared to the same in wild-type mice. RNA analysis showed that when HCC was exposed to the combined treatment, relatively decreased ABC transporters expression was found. Immunohistochemical staining showed that phosphorylation of STAT5 and ABCB1 were downregulated in HCC tissues, suggesting that GHA in vivo downregulates ABC transporters in HCC, and therefore sensitizes them to sorafenib. Clinical data derived from HCC patients using the TCGA database showed that multiple ABC transporters in both types of cancer correlate with GHR levels; that is, when GHR levels are relatively high, patient survival is significantly decreased. Additionally, higher ABCC1 levels also lead to significantly decreased survival rate in HCC patients. Collectively, the results indicate that a GHA is effective in sensitizing both melanoma and HCC to available treatments in vivo and may be used as a therapeutic strategy for higher efficacy of tumor clearance. Citation Format: Yanrong Qian, Reetobrata Basu, Samuel Mathes, Prateek Kulkarni, Emily Davis, Darlene Berryman, Edward List, Silvana Duran, John J. Kopchick. Growth hormone receptor antagonist sensitizes melanoma and hepatocarcinoma to drug treatments via downregulation of ABC transporters in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2621.
Abstract 5586: Demonstrating restoration of T cell function in exhausted T cells with IKZF3 small molecule inhibitor, Lenalidomide
Authors: Joanne Hay, Francis Acklam, Darryl Turner, Mark Barbour, Preeti Singh, Courtney Grant, Hayley Gooding, Rhoanne McPherson, Justyna Rzepecka
Journal: Cancer Research (2022)

Abstract CD8+ T cell exhaustion as a result of prolonged antigenic stimulation in the tumour microenvironment is thought to be a major mechanism by which tumours can escape immune surveillance. T cell exhaustion is characterised by co-expression of checkpoint inhibitor molecules such as PD-1, LAG-3 and TIM-3; reduced proliferative capacity; and diminished production of pro-inflammatory cytokines such as IL-2, IFN-γ and TNF-α and treatment with checkpoint inhibitor blockade such as Nivolumab (anti-PD-1) have shown great promise in the treatment of a subset of individuals and tumour types. However, resistance to these approaches is prevalent and there is a need to identify novel targets to provide alternative options for the rescue of T cell exhaustion and cancer treatment for use alone or potentially in combination with checkpoint inhibitor modulation. One such target is IKZF3, a transcription factor that is increased in murine models of T cell exhaustion and reduces IL-2 expression. Previously we presented an in vitro human T cell exhaustion assay whereby in vitro stimulated T cells phenotypically and functionally recapitulate the exhausted T cells found within the tumour microenvironment and now we demonstrate that exhaustion can be partially rescued by treatment with the IKZF3 small molecule inhibitor, Lenalidomide, alone and in combination with checkpoint inhibitor blockade. The use of small molecule inhibitors offers new avenues for reversing T cell exhaustion in cases of checkpoint inhibitor resistance and this platform delivers a robust assay allowing for assessment of small molecules or checkpoint inhibitors both individually and in combination. Citation Format: Joanne Hay, Francis Acklam, Darryl Turner, Mark Barbour, Preeti Singh, Courtney Grant, Hayley Gooding, Rhoanne McPherson, Justyna Rzepecka. Demonstrating restoration of T cell function in exhausted T cells with IKZF3 small molecule inhibitor, Lenalidomide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5586.
Abstract 5301: GDF-15 neutralizing antibody restores cancer-induced cachexia
Authors: Guojin Wu, Jinming Liang, Feng He, Meng Zhang, Zhengcheng Guo, Jinying Ning
Journal: Cancer Research (2022)

Abstract Growth and differentiation factor 15 (GDF-15) is a member of the transforming growth factor β superfamily. Elevated GDF-15 level was often the result of pathological conditions, including autoimmune disease and cancer. Increased GDF-15 caused metabiotic disorders such as anorexia and cachexia, and GDF-15 became an attractive target for metabolic intervention. Here, we developed a humanized GDF-15 neutralizing antibody (H53E5-8V2) from hybridoma of mice immunized with GDF-15-mFc. H53E5-8V2 had high affinity to GDF-15 (Kd=0.05nM), and demonstrated a stronger binding to coated GDF-15-HIS than Ponsegnomab (Pfizer Inc.) with ELISA assay (EC50=0.33nM vs 0.73nM). H53E5-8V2 also had strong binding to cynoGDF15 (EC50=0.3nM). In ELISA blocking assay, H53E5-8V2 disrupted the interaction of GDF-15 and GFRAL with a lower concentration than Ponsegnomab (EC50=0.25nM vs. 0.5nM). In addition, H53E5-8V2 neutralized GDF-15 in the culture medium and blocked GDF-15 induced GFRAL signaling more efficiently than Ponsegnomab in reporter cell assay (EC50=0.13nM vs. 0.27nM). H53E5-8V2 was stable and had a serum half-life of 9 days in mice with a single antibody injection. And it prevented body weight decrease of the mouse with HT1080 xenograft tumor, MC38 overexpressing GDF-15, or subcutaneous injection of protein GDF-15 fused with mouse Fc at C terminal. These results suggested that H53E5-8V2 was a good candidate drug for the treatment of cachexia. Citation Format: Guojin Wu, Jinming Liang, Feng He, Meng Zhang, Zhengcheng Guo, Jinying Ning. GDF-15 neutralizing antibody restores cancer-induced cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5301.
Abstract 3095: Breaking the crosstalk of the cellular tumorigenic network in NSCLC by a highly effective drug combination
Authors: Dennis Gürgen, Theresia Conrad, Michael Becker, Susanne Sebens, Christoph Röcken, Jens Hoffmann, Stefan Langhammer
Journal: Cancer Research (2022)

Abstract Background: Non-small cell lung cancer (NSCLC) is commonly diagnosed at advanced stages with limited treatment options particularly in tumors without targetable driver mutations. Methods: Considering previously published criteria for selecting drug combinations for overcoming drug resistances1, we have established a low dose combination therapy with cabozantinib, afatinib, etoricoxib and plerixafor. Utilizing NSCLC patient-derived xenograft (PDX) models we aimed to use this drug regimen to disrupt paracrine substitutional signaling within the tumorigenic network in order to circumvent pre-existing and adaptive drug resistances. In contrast to daily dosing for respective monotherapies the low dose treatment was paused every five days for two days. Result: All PDX tumors treated, including highly therapy-resistant adeno- and squamous cell carcinomas without identifiable driver mutations, were completely suppressed by this drug regimen leading to an Objective Response Rate of 81% and a Clinical Benefit Rate of 100%. After treatment discontinuation growth suppression remained until the end of the follow-up period with only slight increase in tumor growth. The application and the safety profile of this low dose therapy regimen was well manageable and without pronounced side effects in this pre-clinical setting. Discussion: For the first time we show that simultaneous inhibition of pathways forming the cellular tumorigenic network in NSCLC tumors is highly effective and overcomes drug resistances for monotherapies. All of the drugs used in this combination regimen are approved for different indications and therefore readily available. Conclusion: Our results emphatically encourage a setup for a clinical study in advanced stage NSCLC patients without targetable driver mutations combining the drugs cabozantinib, afatinib, plerixafor and etoricoxib in a low dose treatment regimen as novel therapy strategy. Indication of Source: 1. Langhammer S and Scheerer J. Oncotarget 8, 43555-43570 (2017). Citation Format: Dennis Gürgen, Theresia Conrad, Michael Becker, Susanne Sebens, Christoph Röcken, Jens Hoffmann, Stefan Langhammer. Breaking the crosstalk of the cellular tumorigenic network in NSCLC by a highly effective drug combination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3095.
Abstract 1356: In vivo epigenetic CRISPR screen identifies PRMT5 as an immune suppressor in pancreatic cancer
Authors: Hai Hu, Jiehui Deng, Fei Li, wei wang, Alireza Khodadadi-Jamayran
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDA) is a devastating disease in which the mortality rate approaches the incidence rate. Desmoplasia is a hallmark of PDA, which creates a mechanical barrier surrounding the tumor cells, prevents appropriate vascularization and leads to pool immune infiltration. PDA exhibits a “cold” tumor microenvironment characterized by a prominent myeloid cell infiltration, which is extremely immune suppressive. Therefore, PDA has been demonstrated to be resistant to immunotherapy. Indeed, single-agent immune checkpoint inhibitor therapy has failed in clinical trials for PDA patients. Targeting epigenetic modification is an attractive approach to enable the response to immunotherapy in multiple solid tumor models. To identify epigenetic modulators as potential novel immunotherapeutic targets in PDA, we performed an orthotopic in vivo epigenetic CRISPR screen. Prmt5 was screened out as one of the top candidates. Further validation studies showed that Prmt5 knockdown (KD) alone or in combination with anti PD-1 treatment significantly inhibited the tumor progression. PRMT5 shRNA in combination with PD1 blockade can dramatically altered the tumor immune microenvironment (TME) with influx of effector CD8 T cells and changes in the macrophage/myeloid populations. Collectively, our work describes PRMT5 as an attracting target which governs tumor immunity in PDA. Citation Format: Hai Hu, Jiehui Deng, Fei Li, wei wang, Alireza Khodadadi-Jamayran. In vivo epigenetic CRISPR screen identifies PRMT5 as an immune suppressor in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1356.
Abstract 1752: Switchable binding of TecApta to Atezolizumab provides the possibility of enhancing the therapeutic effects of this immune checkpoint inhibitor
Authors: Mohammad Sadegh Atefi, Sola Takahashi, David Sich, Jessica Grondin, Rami Doueiri, Lindsay Bourgeois, Gary Olsem, Akiko Futamura, Julie Yang, Joan Oliva, John Elshimali, Carlos Pereira
Journal: Cancer Research (2022)

Abstract One of the main goals of cancer therapeutics is to develop smart molecules that can deliver drugs or immunogens to cancer cells within the tumor, while avoiding the toxicity to normal cells. Lately, immune checkpoint inhibitors have shown significant effects in the field of cancer treatment. Atezolizumab is an immune check point inhibitor specific to PD-L1. In order to potentiate anti-tumor aspects of Atezolizumab, we have developed TecApta, a switchable single strand DNA oligonucleotide aptamer that specifically binds to this antibody with a high affinity and specificity. However, TecApta is detached from Atezolizumab upon binding of this antibody to its target PD-L1. This switchable aspect of TecApta makes it a suitable drug carrier for targeting cancer cells within the tumor microenvironment. We have developed modified versions of TecApta which include either the chemotherapy drug, gemcitabine, or the immune activator, TLR9A. Based on our in vitro data, both versions are biologically active. The gemcitabine sensitive cell line MDA-MB-231/Luc exhibits similar IC50s (20nM) for both gemcitabine-linked-TecApta (GMZ-TecApta) and the free unbound gemcitabine. Moreover, the same concentrations of TLR9A-linked-TecApta (TLR9A-TecApta) and the free TLR9A show similar effects in inducing TLR9 receptors in a cell-based assay. These results suggest that possibly GMZ-TecApta and TLR9A-TecApta can be carried by Atezolizumab and released within the tumor microenvironment, where they may induce apoptosis or aggravate an immune reaction, respectively. Animal studies will be conducted in the future to investigate the possibility of such favorable outcomes. Citation Format: Mohammad Sadegh Atefi, Sola Takahashi, David Sich, Jessica Grondin, Rami Doueiri, Lindsay Bourgeois, Gary Olsem, Akiko Futamura, Julie Yang, Joan Oliva, John Elshimali, Carlos Pereira. Switchable binding of TecApta to Atezolizumab provides the possibility of enhancing the therapeutic effects of this immune checkpoint inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1752.
Abstract 5626: Acquisition of lymphatic phenotype in bone marrow endothelial progenitors is regulated by immunosuppressive Th2 cytokines
Authors: Maria Espinoza Gonzalez, Lisa Volk-Draper, Nihit Bhattarai, Sophia Ran
Journal: Cancer Research (2022)

Abstract Introduction: Myeloid-lymphatic endothelial progenitors (M-LECPs) significantly contribute to expansion of tumor lymphatics and metastasis to lymph nodes. Bone marrow (BM) generated M-LECPs are a subset of M2-type of tumor-associated macrophages (TAMs) that heavily infiltrate breast and other human cancers. The M2-type of TAMs is primarily induced by immunosuppressive Th2 cytokines IL-4, IL-13, and IL-10. The goal of this study was to determine whether Th2 factors also promote the lymphatic phenotype in precursors of M-LECPs. Methods: Mouse BM cells were differentiated into M-LECPs by priming with CSF-1 followed by activation of LPS-TLR4 pathway. Transcripts of IL-4, IL-13, and IL-10 were measured by qPCR, and their proteins secreted into conditioned medium were detected by ELISA. The levels of receptors for Th2 cytokines IL-4, IL-13, and IL-10 as well as for stem cells (CD117, Sca-1), M2-TAMs (CD204, CD206) and lymphatic endothelial cells (Lyve-1, podoplanin, integrin-9a, collectin-12 and stabilin-1) were quantified by qPCR and flow cytometry. Impact of TLR4 induced autocrine IL-10 pathway was determined by analyzing the surface markers and gene profiles of differentiated M-LECPs in the presence of IL-10 blocking or control antibodies. Tumor levels of Th2 cytokines and expression of Th2 receptors in Lyve-1+ progenitors were detected by ELISA and immunofluorescence, respectively. Results: More than 95% of myeloid precursors treated with CSF-1 and LPS upregulated all three Th2 receptors and IL-10 but not IL-4 or IL-13 ligands. All receptors were functional as indicated by upregulation of M2, immunosuppressive, lymphatic and stem markers in cells co-treated with exogenous Th2 ligands as compared with CSF-1 alone. Blocking autocrine IL-10 significantly suppressed both M2-specific and pro-lymphatic differentiation. Tumor-infiltrating M-LECPs expressed Th2 receptors as well as all corresponding ligands including IL-4 and IL-13 that were absent in the BM cells. Conclusion: These data present a novel evidence that activation of immunosuppressive Th2 pathways in BM myeloid precursors induces both the M2-type and lymphatic phenotype. Expansion of lymphatics can enhance tumor immunosuppression by physical removal of immunostimulatory cells. These findings suggest that targeting Th2 pathways can simultaneously relieve immunosuppression and inhibit differentiation of pro-lymphatic progenitors that promote metastasis. Citation Format: Maria Espinoza Gonzalez, Lisa Volk-Draper, Nihit Bhattarai, Sophia Ran. Acquisition of lymphatic phenotype in bone marrow endothelial progenitors is regulated by immunosuppressive Th2 cytokines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5626.
Abstract 170: Development of diacylglycerol kinase assays to facilitate isoform specific inhibitor discovery
Authors: Safnas F. AbdulSalam, Mia M. Eason, Holly A. Fowle, Anna L. Stuart, Kurumi Y. Horiuchi
Journal: Cancer Research (2022)

Abstract Diacylglycerol (DAG) and phosphatidic acid (PA) are two key second messengers in signaling and metabolic pathways. Diacylglycerol kinase (DGK) phosphorylate DAG to produce PA, acting as a central switch between the various signal transduction pathways activated by these second messengers. Ten DGK isoforms (α, β, γ, δ, ε, ζ, η, θ, ι, and κ) have been identified and categorized into five classes based on their structural features. DGKα is highly expressed in several cancers including hepatoma, lymphoma and melanoma, and has been shown to promote cancer survival by positively regulating proliferative activity through several signaling pathways, attracting interest to DGKα as a potential therapeutic target. DGKα and ζ are expressed at high levels in T cells, and shown to promote T cell anergy, pointing to inhibition of these DGK isoforms as a means of enhancing T cell anti-tumor activity and restoring T cells function. Several DGK isoforms have also been implicated in disease contexts such as hypertension, autoimmunity, type II diabetes, epilepsy, and bipolar disorder. Current DGK inhibitor discovery efforts are focused on DGKα and ζ, but to our knowledge no compounds have proceeded to clinical trial-to date. To facilitate these efforts, we have developed a DGK screening panel including compound profiling assays for all DGK isoforms. This is an essential tool for identification of potent and isoform selective inhibitors towards therapeutically relevant DGK isoforms. Further, we present kinetic characterization of all isoforms and lipid substrate specificity studies of DGKs. Citation Format: Safnas F. AbdulSalam, Mia M. Eason, Holly A. Fowle, Anna L. Stuart, Kurumi Y. Horiuchi. Development of diacylglycerol kinase assays to facilitate isoform specific inhibitor discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 170.